It is assumed that not less than 50% of adults are infected with human papillomavirus (HPV) in the world and, among papillomaviruses, particularly four types of HPV 16, 18, 31 and 45 have been confirmed to cause not less than 80% of cervical cancer (non-patent document 1).
All over the world, cervical cancer is a cancer that highly frequently occurs in women next to breast cancer and, according to the World Health Organization, not less than 500,000 cervical cancer patients are produced every year worldwide and not less than 300,000 people are assumed to die of cervical cancer every year. Particularly in developing countries and less developed countries, it is the main cause of death of women (non-patent document 2). According to the IARC statistics, it is reported that a method most effective for eradicating HPV infection for a long term in developing countries particularly where the number of chronically infected people is extremely high as compared to advanced countries is administration of HPV preventive vaccines.
Methods for vaccine development relating to cervical cancer largely focus on two: prophylactic vaccine and therapeutic vaccine. Prophylactic vaccine aims to prevent a host from being infected with HPV by a strong neutralizing antibody produced by HPV L1/L2 antigen protein. On the other hand, therapeutic vaccine targeting HPV E6/E7 aims to induce specific cellular immunity to prevent progression of disease when infection with HPV has been confirmed, or cause regression of lesion already formed and malignant tumor.
Since E6/E7 protein of HPV is a cancer specific antigen involved in canceration of cells infected with HPV and the like, therapeutic vaccine utilizing E6/E7 protein as a target of cervical cancer immunotherapy has been studied. In fact, reports have documented that administration of HPV E6/E7 protein synthesized by a microorganism system to a rat injected with tumor cells inhibited or delayed tumor formation (non-patent documents 3, 4 and 5).
In consideration of the fact that people infected with HPV are mainly concentrated in less developed countries, the development of a method of producing a vaccine to HPV economically and stably is strongly demanded for the prophylaxis and treatment of cervical cancer caused by papillomavirus.
The present inventors developed a therapeutic vaccine for cervical cancer containing a killed lactic acid bacterium expressing E7 protein of HPV on the surface as an active ingredient. This therapeutic vaccine is orally administered to cause uptake of the E7 protein into patients via the intestine and induce specific cellular immunity to the E7 protein in the cervix, thereby preventing patients infected with HPV (e.g., patients having cervical cancer precancerous lesion CIN3) from shift to cervical cancer. The vaccine shows superior safety and effectiveness in clinical tests (non-patent document 6).
At present, in an undergoing exploratory clinical test, the production cost of a preparation of a killed lactic acid bacterium expressing E7 protein of HPV, which is the active ingredient of the oral therapeutic vaccine, on the surface is comparatively expensive. If efficacy equivalent to the effectiveness at present can be shown even by reducing the dose from that in the exploratory clinical test (four 250 mg capsules, once per day), the cost of the preparation becomes lower, practicalization of the therapeutic drug becomes higher, and an economical burden on patients can be reduced.
On the contrary, uptake of orally ingested fine particles into the body via the intestine is regulated by mesentery M cell permeability of the fine particles. It is known that particles having a size exceeding 10 μm show markedly low phagocytosis by M cell (non-patent document 7).